ES2926579T3 - Process for the preparation of intermediate compounds useful in the preparation of inhibitors of the Hepatitis C virus (HCV) - Google Patents

Abstract

The present invention relates generally to a process for the preparation of 9-halo-3-(2-haloacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one of the formula I, which is an intermediate in the preparation of hepatitis C virus (HCV) inhibitors. (Automatic translation with Google Translate, without legal value)

Description

DESCRIPTION

Process for the preparation of intermediate compounds useful in the preparation of Hepatitis C virus (HCV) inhibitors

Cross reference with related requests

This application is related to and claims the benefit of the filing date of United States Provisional Patent Application No. 62/332,193, filed May 5, 2016, entitled "Process for the Preparation of Intermediates Useful in the Preparation of Hepatitis C Virus (HCV) Inhibitors".

Background of the invention

field of invention

The present invention generally relates to a process for the preparation of 9-halo-3-(2-haloacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one of Formula I , which is an intermediate compound used in the preparation of Hepatitis C Virus (HCV) inhibitors, particularly used in the preparation of Velpatasvir of Formula A.

Description of Related Art

The compound 9-halo-3-(2-haloacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one of Formula I is used as an intermediate in the preparation of Velpatasvir from Formula A. The structural identification of 9-halo-3-(2-haloacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one of Formula I, where 'X ' represents a halogen; is represented as follows:

Formula I

Velpatasvir is chemically known as {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino-] -2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromene[4',3':6,7]naphtho[1,2-d methyl ]imidazol-2-yl)-5-methylpyrroli-din-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate; represented by the following structure:

Velpatasvir is an investigational pangenotypic NS5A inhibitor and is currently in clinical trials in combination with the nucleotide analog polymerase inhibitor sofosbuvir (SOF), approved as Sovaldi®, for the treatment of chronic hepatitis C virus infection. HCV of genotype 1-6.

U.S. Patent Nos. 8,940,718 ("the '718 patent"), 8,575,135 ("the '135 patent") and 8,921,341 ("the '341 patent") disclose new therapeutic agents against HCV such as Velpatasvir of Formula A and its intermediate compound of Formula I, and processes for their preparation. The process disclosed for the preparation of the compound of Formula I in the '718 patent is schematically represented as follows:

Scheme 1

[0007] PCT Publication No. 2015/191437 ("the '437 publication") discloses a process for the preparation of the compound of Formula I. The process disclosed in the '437 publication is schematically depicted as follows:

Scheme 2

The processes described above have certain disadvantages since they involve the use of expensive starting materials and multiple palladium-catalyzed reactions, which are not feasible in profitable operations on a commercial scale.

Therefore, there is a need in the art to provide a process for the preparation of intermediates useful in the preparation of HCV inhibitors, which does not rely on the use of expensive starting materials and other difficulties, and which is readily compatible with commercial scale operations.

Among other aspects of the present invention, the present invention simplifies the process for the preparation of the compound of Formula I with higher yield and high purity through the use of new intermediate compounds of Formula IV, IVa and V.

Summary of the invention

According to one embodiment, the present invention provides a process for the preparation of a compound of Formula I, wherein 'X' represents a halogen:

Formula I

comprising:

a) reacting a compound of Formula II with a compound of Formula III to obtain a compound of Formula IV, where 'X' represents a halogen,

b) cyclizing the compound of Formula IV to obtain a compound of Formula V,

c) converting the compound of Formula V to a compound of Formula VI, and

d) converting the compound of Formula VI to the compound of Formula I.

According to another embodiment, described herein, there is provided a process for the preparation of a compound of Formula I, wherein 'X' represents a halogen, comprising:

a) reacting a compound of Formula II with a compound of Formula III to obtain a compound of Formula IV, where 'X' represents a halogen,

b) cyclizing the compound of Formula IV to obtain a compound of Formula V, and

c) converting the compound of Formula V to the compound of Formula I.

According to another embodiment, described herein, there is provided a process for the preparation of a compound of Formula I, wherein 'X' represents a halogen, comprising:

a) reacting a compound of Formula II with a compound of Formula III to obtain a compound of Formula IV, where 'X' represents a halogen, and

b) converting the compound of Formula IV to the compound of Formula I.

According to another embodiment, the present invention provides a process for the preparation of a compound of Formula Ia:

comprising:

a) reacting a compound of Formula IIa with a compound of Formula III to obtain a compound of Formula IVa,

Formula IIa

b) cyclizing the compound of Formula IVa to obtain a compound of Formula V,

c) converting the compound of Formula V to a compound of Formula VI, and

d) converting the compound of Formula VI to the compound of Formula I.

According to another embodiment, the present invention provides a compound of Formula IV, wherein 'X' represents a halogen,

According to another embodiment, the present invention provides a compound of Formula IVa,

According to another embodiment, the present invention provides a compound of Formula V,

According to another embodiment described herein, a process for the preparation of Velpatasvir of Formula A is provided, comprising preparing 9-halo-3-(2-haloacetyl)-10,11-dihydro-5H-dibenzo[ c,g]chromen-8(9H)-one of Formula I according to the process described above, and converting 9-halo-3-(2-haloacetyl)-10,11-dihydro-5H-dibenzo[c, g]chromen-8(9H)-one of Formula I in Velpatasvir of Formula A.

According to another embodiment described herein, a pharmaceutical composition useful for inhibiting HCV is provided, comprising Velpatasvir of Formula A, prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.

Detailed description of the invention

The present invention provides a process for the preparation of a compound of Formula I using novel intermediate compounds. Furthermore, the conversion of the compound of Formula I to Velpatasvir of Formula A is described herein.

According to one embodiment, the present invention provides a process for the preparation of the compound of Formula I, wherein 'X' represents a halogen:

Formula I

comprising:

a) reacting a compound of Formula II with a compound of Formula III to obtain a compound of Formula IV, where 'X' represents a halogen,

b) cyclizing the compound of Formula IV to obtain a compound of Formula V,

c) converting the compound of Formula V to a compound of Formula VI, and

d) converting the compound of Formula VI to the compound of Formula I.

The starting material of the compound of Formula II and Formula III is known in the art and can be prepared by any known method. For example, the compound of Formula II can be synthesized as disclosed in US Patent No. 6,387,926, or it can be by the process described in the present application. The compound of Formula III can be synthesized as disclosed in the Journal of Medicinal Chemistry, 1998, vol. 41, #7, pages 1068 - 1083.

Unless otherwise specified, the term 'X' represents a halogen, which is selected from fluorine (F), chlorine (Cl), bromine (Br) and iodine (i).

In a preferred embodiment, the compound of Formula II and Formula IV may be represented as follows:

The starting compound of Formula lia of the present invention can be prepared from 4-bromo-3-methylbenzonitrile by bromination as described in the following process.

In another embodiment, the present invention provides a process for the preparation of a compound of Formula lia, comprising: brominating 4-bromo-3-methylbenzonitrile in the presence of 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) and optionally in the presence of a catalyst in a suitable solvent to obtain the compound of Formula IIa.

Examples of catalysts used herein for the bromination step include, but are not limited to, 2,2'-azobis(2-methylpropionitrile) (AIBN), 1,1'-azobis(cyclohexane carbonitrile) (ACCN), 4,4'-azobis(4-cyanovaleric acid), 4,4'-azobis(4-cyanovaleric acid), 1,1'-azobis(cyclohexanecarbonitrile), 2,2'-azobis(2-methylpropionamidine) dihydrochloride, ammonium persulfate, tert-butyl hydroperoxide, manganese dioxide, aluminum chloride, and the like, and mixtures thereof.

Suitable solvents for bromination include, but are not limited to, amides, nitriles, ethers, halogenated hydrocarbons, and mixtures thereof. Suitable amides include, but are not limited to, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, and the like, and mixtures thereof. Suitable nitriles include, but are not limited to, acetonitrile, propionitrile, benzonitrile, and the like, and mixtures thereof. suitable ethers they include, but are not limited to, tetrahydrofuran, dimethyl ether, diisopropyl ether, tertiary butyl methyl ether, 1,4-dioxane, and the like, and mixtures thereof. Suitable halogenated hydrocarbons include, but are not limited to, methylene chloride, ethylene chloride, chloroform, and the like, and mixtures thereof.

The bromination reaction is advantageously carried out at a temperature of from about 0°C to reflux temperature, preferably at 85°C or less.

The resulting compound of Formula IIa can be directly further processed without isolation from the reaction solution.

Alternatively, the compound of Formula IIa can be isolated as a solid and used for further reaction. The isolation step includes washing the organic layer with an aqueous base solution followed by concentration of the organic layer in vacuo to obtain the residue by any method known in the art, at the end of the reaction. For example, distillation, evaporation, rotary drying (such as with the Büchi rotary evaporator), flash drying, rotary flash drying and the like, preferably vacuum distillation. The resulting residue can be crystallized or suspended using a suitable organic solvent, for example, a mixture of an ether solvent and a cyclic hydrocarbon solvent; preferably from a mixture of tertiary butyl methyl ether and heptane.

Step a) of the aforementioned process involves the reaction of the compound of Formula II, preferably the compound of Formula IIa, with the compound of Formula III, to obtain a compound of Formula IV, preferably a compound of Formula IVa, in the presence of a suitable base and in a suitable solvent.

Examples of suitable bases used herein for the step of reacting the compound of Formula IIa with the compound of Formula III include, but are not limited to, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, tert -sodium butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine and the like, and mixtures thereof.

Suitable solvents for the reaction of the compound of Formula IIa with the compound of Formula III include, but are not limited to, amides, nitriles, ethers, aromatic hydrocarbons, and mixtures thereof. Suitable amides include, but are not limited to, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, and the like, and mixtures thereof. Suitable nitriles include, but are not limited to, acetonitrile, propionitrile, and the like, and mixtures thereof. Suitable ethers include, but are not limited to, tetrahydrofuran, 2-methyltetrahydrofuran, tertiary butyl methyl ether, 1,4-dioxane, and the like, and mixtures thereof. Suitable aromatic hydrocarbons include, but are not limited to, toluene, xylene, and the like, and mixtures thereof.

The reaction of the compound of Formula IIa with the compound of Formula III is preferably carried out at a temperature of from about 25°C to reflux temperature.

Step b) of the aforementioned process involves the cyclization of the compound of Formula IV, preferably the compound of Formula IVa, to obtain the compound of Formula V in the presence of a suitable palladium catalyst, a suitable base and a suitable solvent at a temperature preferably from about 25°C to reflux temperature.

Suitable palladium catalyst used herein is selected from the group consisting of tetrakis(triphenylphosphine)palladium(0), tetrakis(tri(otolyl)phosphine)palladium(0), Pd2(dba)3, [1,1 '-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (Pd(dppf)2Ch), palladium(II) acetate, and the like, and mixtures thereof.

Suitable bases used herein for the cyclization of the compound of Formula IVa include, but are not limited to, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like, and mixtures thereof; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and the like, and mixtures thereof; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like, and mixtures thereof; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like, and mixtures thereof; and organic bases such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, and the like, and mixtures thereof.

Suitable solvents for the cyclization of the compound of Formula IVa include, but are not limited to, ethers, amides, aromatic hydrocarbons, water, and mixtures thereof. Suitable ethers include, but are not limited to, tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, tertiary butyl methyl ether, 1,4-dioxane, 1,2-dimethoxyethane, and the like, and mixtures thereof. Suitable amides include, but are not limited to, dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidinone, and the like, and mixtures thereof. Suitable aromatic hydrocarbons include, but are not limited to, toluene, xylene; and the like, and mixtures thereof.

Step c) of the aforementioned process involves converting the compound of Formula V to the compound of Formula VI in the presence of methylmagnesium halide, particularly methylmagnesium bromide in a suitable solvent.

Suitable solvents used for step c) include, but are not limited to, ethers such as tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, tertiary butyl methyl ether, 1,4-dioxane, 1,2-dimethoxyethane and the like. and mixtures thereof.

Step c) is preferably carried out at a temperature of about 0°C to reflux temperature.

Step c) optionally involves protecting the keto group on the compound of Formula V and then reacting with methylmagnesium halide, followed by in situ deprotection of the protecting group to obtain the compound of Formula VI.

Protection of the keto group in the compound of Formula V is preferably carried out at a temperature of from about 0°C to reflux temperature.

Suitable keto protecting group used herein is selected from dimethyl acetals, diethyl acetals, 1,3-dioxanes, 1,3-dioxolanes, 1,3-dithianos, 1,3-dithiolanes, trimethylsilyl, triethylsilyl and the like.

Protection of the keto group in the compound of Formula V can be carried out in the presence of a suitable base, including, but not limited to, lithium bis(trimethylsilyl)amide, lithium diisopropylamide, lithium tetramethylpiperidide, bis(trimethylsilyl )sodium amide, potassium bis(trimethylsilyl)amide, sodium hydride, potassium hydride and the like, and mixtures thereof.

The deprotection of the keto group can be carried out in the presence of a suitable deprotecting agent. Suitable deprotecting agent includes, but is not limited to, acids such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, and the like, and mixtures thereof.

Step d) of the aforementioned process involves converting the compound of Formula VI to the compound of Formula I by any process known in the art, for example, the processes taught in the aforementioned '718 patent and '437 PCT application.

In another embodiment, the present invention provides a compound of Formula IV, where 'X' represents a halogen,

In another embodiment, the present invention provides a compound of Formula IVa,

Formula IVa

In another embodiment, the present invention provides a compound of Formula V,

In another embodiment, described herein, a process for the preparation of Velpatasvir is provided, comprising: preparing the 9-halo-3-(2-haloacetyl)-10,11-dihydro-5H-dibenzo[c,g ]chromen-8(9H)-one of Formula I as described above, and converting the 9-halo-3-(2-haloacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)one in Velpatasvir by any process known in the art, for example, the processes shown in the aforementioned '718 patent and '437 PCT application.

In another embodiment, described herein, a pharmaceutical composition is provided comprising Velpatasvir of Formula A prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.

examples

The following examples describe in detail the processes that can be used in the preparation of the compounds described above.

Example 1:

Preparation of 4-bromo-3-(bromomethyl)-benzonitrile

4-Bromo-3-methylbenzonitrile (80 g), 1,3-dibromo-5,5-dimethylhydantoin (70 g), azobisisobutyronitrile (6.7 g), and ethylene chloride (650 mL) were combined in a 1 liter reaction flask. L. Then, the reaction mixture was heated to 80-85 °C and stirred for 19 hours at the same temperature. The reaction mixture was allowed to cool to 20-25°C and washed with saturated aqueous sodium bicarbonate solution (650 mL) followed by water (650 mL). The organic layer was separated and concentrated to a dark brown oil, which solidified on standing. The resulting solid was stirred in a mixture of tert-butyl methyl ether (40 mL) and heptane (80 mL) for 3 hours. The resulting suspension was filtered and the filter cake washed with heptane (80 mL). The filter cake was dried in a vacuum oven at 35°C to obtain the title compound. Yield: 51.3g; HPLC purity: 95.1%; 1H NMR (300 MHz, CDCh) 87.73 (d, 1H, J = 2.0 Hz), 7.70 (d, 1H, J = 8.3 Hz), 7.42 (dd, 1H, J = 8.3, 2.0 Hz), 4.56 (s, 2H).

Example 2:

Preparation of 4-bromo-3-(bromomethyl)-benzonitrile

4-Bromo-3-methylbenzonitrile (9.8 g), 1,3-dibromo-5,5-dimethylhydantoin (7 g), and 1,2-dichloroethane (80 mL) were combined in a 1 L reaction flask and shaken. under nitrogen at 10 - 15 °C. 2,2'-azobis(2-methylpropionitrile) (0.82 g) was added to the reaction mass and the reaction mixture was heated to 80-85 °C. After completion of the reaction, the reaction mixture was filtered to remove 5,5-dimethylhydantoin (4.2 g). The mother liquor was used in the next step without further purification (Yield: 12 g w/w assay).

Example 3:

Preparation of 7-(2-bromo-5-cyanobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one

7-Hydroxy-1-tetralone (26 g) and potassium carbonate (44 g) in N,N-dimethylacetamide (130 mL) were combined in a 1 L reaction flask. To the reaction mass was added a solution in 4-bromo-3-(bromomethyl)benzonitrile dimethylacetamide (44 g in 130 mL) at 25-30 °C. The resulting reaction mixture was stirred at room temperature for 68h. Water (520 mL) was added to the reaction mixture at 8-12 °C over 25 min and stirred for 30 min at 10 °C. The precipitated solid was filtered and water (300 mL) was added to the solid and stirred for 45 min. The solid was filtered and washed with water (50 mL) and dried at 35 °C under vacuum for ca. 24 h to obtain the title compound. Yield: 58.7g; HPLC purity: 98.2%; 1H NMR (300 MHz, CDCla) 87.85 (m, 1H), 7.71 (d, 1H, J = 8.2 Hz), 7.58 (d, 1H, J = 2.7 Hz), 7.46 (dd, 1H, J = 8.2, 2.0 Hz), 7.23 (d, 1H, J = 10.4 Hz), 7.16 (dd, 1H, J = 8.4, 2.7 Hz), 5.13 (s, 2H), 2.93 (dd, 1H, J = 6.0, 6.0 Hz), 2.65 (dd, 1H, J = 6.5,6.5 Hz), 2.13 (pent., 2H, J = 6.3 Hz).

Example 4:

Preparation of 7-(2-bromo-5-cyanobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one

7-Hydroxy-1-tetralone (29.5 g) and potassium carbonate (50 g) in N,N-dimethylacetamide (150 mL) were combined in a 1 L reaction flask. To the reaction mass was added a solution in 4-bromo-3-(bromomethyl)benzonitrile dimethylacetamide (50 g in 160 mL) at 20-25 °C for 43 min. The reaction mixture was stirred at 20 °C for 21 h. After the completion of the reaction, water (620 mL) was added to the reaction mass at 12 °C and the mixture was stirred at 1 2 -15 °C for 30 min. The precipitated solid was collected by filtration and washed with water (3 x 30 mL) and dried in vacuo at 30 °C. The solid was then stirred in heptane (780 mL) at 25 °C for 5 h, filtered, washed with heptane (3 x 50 mL) and air-dried for 3 days. The heptane slurry (1 x 620 mL and 1 x 540 mL) was repeated and dried to give the title compound. Yield: 51.8g; HPLC purity: 93%.

The above solid was dissolved in isopropyl acetate (600 mL) at 80-85°C and the temperature of the reaction mass was allowed to cool to 25-30°C. The precipitated solid was filtered and washed with isopropyl acetate (35 mL) and vacuum dried at 40 °C for 3 h to obtain the title compound. Yield: 40.9g; HPLC purity: 97.9%.

Example 5:

Preparation of 3-cyano-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one

Combined 7-(2-bromo-5-cyanobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one (1.32 kg), potassium carbonate (1.02 kg), pivalic acid (113.5 g), PPh3 (29.1 g ) and N,N-dimethylacetamide (6.6 L) in a 20 L reaction flask. Pd(AcO)2 (24.9 g) was added to the reaction mass and then the reaction mixture was heated to 115-120 °C and stirred for 1.5 hours at the same temperature. After the reaction was complete, the reaction mass was allowed to cool to 10 °C and a mixture of methylene chloride (39.6 L) and water (13.2 L) was added. The organic and aqueous layers were separated and the aqueous layer was extracted with methylene chloride (6.6 L). The combined organic layer was washed with 20% sodium chloride solution (6.6 L), then filtered. The obtained filtrate was distilled off in vacuo to obtain the title compound.

Example 6:

Preparation of 3-acetyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9)-one

3-Cyano-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (50 g), copper (I) bromide (2.61 g), and tetrahydrofuran (500 mL) were combined in a 1L reaction flask was allowed to cool to 0°C and stirred for 30 min at the same temperature. 1.0 M lithium bis(trimethylsilyl)amide in tetrahydrofuran (200 mL) was added to the reaction mass at 0 °C, and the reaction mass was heated to 20 °C and stirred for 20 min at the same temperature. Chlorotrimethylsilane (25.4 mL) was added to the reaction mass at 15 °C and stirred for 10 min at 20 °C followed by 3.4 M methylmagnesium bromide in 2-methyltetrahydrofuran (160 mL) which was added over 1 hour at 15 °C and stirred for 16 h at 20 °C. Then, the reaction mass was slowly added to pre-cooled 2M aqueous hydrochloric acid (500 mL) below 20°C and stirred for 5 hours at the same temperature. Then the precipitated solid was filtered and washed with water (100 mL) and methanol (100 mL) and dried to obtain the title compound.

The filtrate was taken to a reaction flask and allowed to cool to -20 °C and stirred for 18 h at the same temperature and the precipitated solid was filtered and washed with methanol (20 mL) and the wet compound was dried to obtain the title compound. Yield: 41.8g; HPLC purity: 98.5%.

Example 7:

Preparation of 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9)-one

3-Acetyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9)-one (5 g) was dissolved in a 9:1 mixture of methylene chloride and methanol (35 mL) at 20 °C A solution of pyridinium tribromide in methylene chloride was added dropwise to the reaction mass at 20°C, and the reaction mass was stirred for 30 min at 25°C. After the completion of the reaction, the precipitated solid was filtered off and washed with methanol (2 x 25 mL) to obtain the title compound. Yield: 6.1g; HPLC purity: 98%.

Claims (12)

1. A process for the preparation of a compound of Formula I comprising: a) reacting a compound of Formula II with a compound of Formula III to obtain a compound of Formula IV, wherein the compound of Formula II is,

where the compound of Formula III is,

where the compound of Formula IV is,

and where 'X' represents a halogen; b) cyclizing the compound of Formula IV to obtain a compound of Formula V, where the compound of Formula V is,

c) converting the compound of Formula V to a compound of Formula VI, where the compound of Formula VI is,

Y d) converting the compound of Formula VI to the compound of Formula I, where the compound of Formula I is

2. The process according to claim 1, wherein: (i) reaction step a) is carried out in the presence of a base and a solvent; Y (ii) conversion step c) is carried out in the presence of methylmagnesium bromide and a solvent; Y (iii) conversion step c) is carried out in the presence of a solvent selected from one of tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, tertiary butyl methyl ether, 1,4-dioxane and 1,2-dimethoxyethane, and mixtures of them. 3. The process according to claim 1, wherein conversion step c) further comprises: protecting the keto group in the compound of Formula V with a protecting group; reacting the protected compound with methylmagnesium halide; Y deprotecting the protecting group in situ to obtain the compound of Formula VI, preferably: (i) where the protection process of the keto group in the compound of Formula V is preferably carried out at a temperature of about 0 °C to reflux temperature; Y (ii) wherein the keto protecting group is selected from one of dimethyl acetal, diethyl acetal, 1,3-dioxane, 1,3-dioxolane, 1,3-dithiane, 1,3-dithiolane, trimethyl silyl and triethylsilyl; Y (iii) where the protection process of the keto group in the compound of Formula V is carried out in the presence of a base selected from one of lithium bis(trimethylsilyl)amide, lithium diisopropylamide, lithium tetramethylpiperidide, bis(trimethylsilyl) sodium amide, potassium bis(trimethylsilyl)amide, sodium hydride and potassium hydride, and mixtures thereof; Y (iv) where the deprotection process of the keto group in the compound of Formula V is carried out using a deprotecting agent selected from hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and pyridinium p-toluenesulfonate, and mixtures thereof. 4. The process according to claim 1, wherein the halogen "X" is one of fluorine, chlorine, bromine and iodine. 5. The process according to claim 1, for the preparation of a compound of Formula I which comprises: a) reacting a compound of Formula Ila with a compound of Formula III to obtain a compound of Formula IVa, where the compound of Formula IIa is,

(Formula lia), where the compound of Formula III is,

(Formula III), where the compound of Formula IVa is,

b) cyclizing the compound of Formula IVa to obtain a compound of Formula V, where the compound of Formula V is,

c) converting the compound of Formula V to a compound of Formula VI, where the compound of Formula VI is,

Y d) converting the compound of Formula VI to the compound of Formula Ia, where the compound of Formula Ia is

6. The process according to claim 5, wherein the compound of Formula IIa is prepared by brominating 4-bromo-3-methylbenzonitrile in the presence of 1,3-dibromo-5,5-dimethylhydantoin (DBDMH), a solvent, and optionally in the presence of a catalyst, preferably: (i) wherein when the catalyst is used, the catalyst is selected from one of 2,2'-azobis(2-methylpropionitrile), 1,1'-azobis(cyclohexanecarbonitrile), 4,4'-azobis(4-cyanovaleric acid ), 4,4'-azobis(4-cyanovaleric acid), 1,1'-azobis(cyclohexanecarbonitrile), 2,2'-azobis(2-methylpropionamidine) dihydrochloride, ammonium persulfate, tert-butyl hydroperoxide, dioxide manganese, and aluminum chloride, and mixtures thereof; Y (ii) where the solvent is selected from one of an amide, a nitrile, an ether and a halogenated hydrocarbon, and mixtures thereof, preferably where the amide is selected from dimethylformamide, dimethylacetamide and N-methylpyrrolidinone, and mixtures thereof; and where the nitrile is selected from acetonitrile, propionitrile and benzonitrile, and mixtures thereof; and wherein the ether is selected from one of tetrahydrofuran, dimethyl ether, diisopropyl ether, tertiary butyl methyl ether, and 1,4-dioxane, and mixtures thereof; and where the halogenated hydrocarbon is selected from one of methylene chloride, ethylene chloride and chloroform, mixtures thereof; and (iii) where the compound of Formula IIa is used without isolating it from the brominating solution, or where the compound of Formula IIa is isolated from the brominating solution by washing the brominating solution with an aqueous base solution, concentrating the resulting solution under vacuum to obtain the solid compound and, optionally, crystallize the solid compound from an organic solvent selected from an ether solvent and a cyclic hydrocarbon solvent. 7. The process according to claim 5, wherein reaction step a) is carried out in an aqueous base selected from one of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, and pyridine, and mixtures thereof; Y where reaction step a) is carried out in a solvent selected from an amide, a nitrile, an ether and an aromatic hydrocarbon, and mixtures thereof, preferably where the amide is selected from dimethylformamide, dimethylacetamide and N-methylpyrrolidinone and mixtures thereof; and where the nitrile is selected from one of acetonitrile and propionitrile, and mixtures thereof; and wherein the ether is selected from one of tetrahydrofuran, 2-methyltetrahydrofuran, tertiary butyl methyl ether and 1,4-dioxane, mixtures thereof; and where the aromatic hydrocarbon is selected from one of toluene and xylene and mixtures thereof. 8. The process according to claim 5, wherein cyclization step b) is carried out in the presence of a palladium catalyst, a base and a solvent, preferably (i) wherein the palladium catalyst is selected from the group consisting of tetrakis(triphenylphosphine) palladium(0), tetrakis(tri(otolyl)phosphine) palladium(0), Pd2(dba)3, [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(N) (Pd(dppf)2Cl2), and palladium(II) acetate, and mixtures thereof; Y (ii) wherein the base is selected from alkali metal hydroxide, alkali metal alkoxide, alkali metal carbonate, alkali metal bicarbonate, and organic base, and mixtures thereof; Y (iii) where the solvent is selected from one of an ether, an amide, an aromatic hydrocarbon and water, and mixtures thereof. 9. A process for the preparation of a compound of Formula Ia comprising: a) reacting a compound of Formula IIa with a compound of Formula III to obtain a compound of Formula IVa, where the compound of Formula IIa is

where the compound of Formula III is

and where the compound of Formula IVa is

b) cyclizing the compound of Formula IVa to obtain a compound of Formula V, where the compound of Formula V is

c) converting the compound of Formula V to a compound of Formula VI, where the compound of Formula VI is

Y d) converting the compound of Formula VI to the compound of Formula Ia, where the compound of Formula Ia is

10. A compound of Formula IV, where 'X' represents a halogen, and where the compound of Formula IV is

11. The compound according to claim 10, wherein the halogen 'X' is bromine. 12. A compound of Formula V, where the compound of Formula V is

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